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Generating Ins2+/−/miR-133aTg Mice to Model miRNA-Driven Cardioprotection of Human Diabetic Heart

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Mouse Genetics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2224))

Abstract

Diabetes mellitus (DM) is caused either due to insulin deficiency (T1DM) or insulin resistance (T2DM). DM increases the risk of heart failure by diabetic cardiomyopathy (DMCM), a cardiac muscle disorder that leads to a progressive decline in diastolic function, and ultimately systolic dysfunction. Mouse models of T1DM and T2DM exhibit clinical signs of DMCM. Growing evidence implicates microRNA (miRNA), an endogenous, non-coding, regulatory RNA, in the pathogenesis and signaling of DMCM. Therefore, inhibiting deleterious miRNAs and mimicking cardioprotective miRNAs could provide a potential therapeutic intervention for DMCM. miRNA-133a (miR-133a) is a highly abundant miRNA in the human heart. It is a cardioprotective miRNA, which is downregulated in the DM heart. It has anti-hypertrophic and anti-fibrotic effects. miR-133a mimic treatment after the onset of early DMCM can reverse histological and clinical signs of the disease in mice. We hypothesized that overexpression of cardiac-specific miR-133a in Ins2+/− Akita (T1DM) mice can prevent progression of DMCM. Here, we describe a method to create and validate cardiac-specific Ins2+/−/miR-133aTg mice to determine whether cardiac-specific miR-133a overexpression prevents development of DMCM. These strategies demonstrate the value of genetic modeling of human disease such as DMCM and evaluate the potential of miRNA as a therapeutic intervention.

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Acknowledgments

This study was supported, in part, by the National Institutes of Health grants HL-113281 and HL-116205 to Paras K. Mishra. We greatly appreciate Dr. Scot Matkovich from the Washington University, St. Louis for his kind gift of cardiac-specific miR-133aTg mice.

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Authors and Affiliations

  1. Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA

    Hamid R. Shahshahan, Tyler N. Kambis, Sumit Kar, Santosh K. Yadav & Paras K. Mishra

Authors
  1. Hamid R. Shahshahan
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  2. Tyler N. Kambis
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  3. Sumit Kar
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  4. Santosh K. Yadav
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  5. Paras K. Mishra
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Corresponding author

Correspondence to Paras K. Mishra .

Editor information

Editors and Affiliations

  1. Basic Research Laboratory, National Cancer Institute, Frederick, MD, USA

    Shree Ram Singh

  2. Department of Surgery, University of California, AntiCancer, Inc., San Diego, CA, USA

    Robert M. Hoffman

  3. Department of Biology, University of Dayton, Dayton, OH, USA

    Amit Singh

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Shahshahan, H.R., Kambis, T.N., Kar, S., Yadav, S.K., Mishra, P.K. (2021). Generating Ins2+/−/miR-133aTg Mice to Model miRNA-Driven Cardioprotection of Human Diabetic Heart. In: Singh, S.R., Hoffman, R.M., Singh, A. (eds) Mouse Genetics . Methods in Molecular Biology, vol 2224. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1008-4_8

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  • DOI: https://doi.org/10.1007/978-1-0716-1008-4_8

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1007-7

  • Online ISBN: 978-1-0716-1008-4

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